An overview of pharmaceutical manufacturing processes and consequent waste generation

1. WASTE GENERATION IN
PHARMACEUTICAL MANUFACTURING
INDUSTRY
by
Vishal Duggal
Alliance Engineers
7812/5, Passi Road, PATIALA (Punjab).
Ph.: 98 140 059 33
email: visduggal@gmail.com; mailto@allianceers.com
for
CESE, IITB
Powai, Mumbai (MS)

2. PHARMACEUTICAL INDUSTRY
 Medications/therapeutic products for humans and
animals
 Manufacture, extraction, processing, purification and
packaging of chemical materials (may include
following);
 Medicinal chemicals and botanical products
 Pharmaceutical active ingredients – resulting from
fermentation, biological and natural extraction, chemical
synthesis, and formulation products
 Biological (and micro-biological) products
 Multiple end-use products – components of formulations,
intermediates, final products
 Cosmetic preparations – containing pharmaceutically active
ingredients (typically intended for treatment of some skin
condition)

3. PHARMACEUTICAL INDUSTRY
 Products or activities specifically excluded from
pharmaceutical manufacturing category are;
 Surgical and medical instruments and apparatus
 Orthopaedic, prosthetic, and surgical appliances and supplies
 Dental equipment and supplies
 Medical/dental laboratory services
 Diagnostic devices
 Food and beverage products fortified with vitamins or other
pharmaceutical active ingredients

4. Pharmaceutical Processes
 Fermentation
 Biological and natural extraction
 Chemical (organic) synthesis
 Physical methods

5. Pharmaceutical Processes
(Fermentation)
 Manufacturing of most antibiotics, steroids, enzymes,
hormones, vitamins, etc.
 Three basic steps
 Inoculum and seed preparation
 Fermentation (including mycelia filteration)
 Product recovery
 Fermentation is a large scale batch process
 Usually begins with a water wash and steam
sterilisation of fermenter vessel
 Usually an exothermic process and needs temperature
control
 Product recovery – solvent extraction, direct
precipitation, ion exchange, adsorption
 Sterilisation – steam is major medium, chemical also

6. Pharmaceutical Processes
(Fermentation) ..
 Fermentation waste off-gases – CO2 and odiferous
substances (e.g., oxides of N and S)
 Scrubbing water from APCE – absorbed chemicals, soluble
organic compounds, insoluble organic oils and waxes
 Solvents used – recovered and reused
 Small fraction of solvents left in aquous phase
 Direct precipitation – Cu and Zn are commonly used
priority pollutant metals
 Occassional infestation of fermentation batch by “phage” –
large amount of wastewaters in very short time (very high
nutrient concentration)
 Spent fermentation broth – sugars, starches, proteins, N,
phosphates
 Sterilizing/cleaning rejects

7. Pharmaceutical Processes
(Fermentation) …
 Commonly used solvents
Acetone Acetonitrile Ammonia (aq.)
n-Amyl acetate Amyl alcohol n-butyl acetate
n-Butyl alcohol Chloroform N,N-Dimethylformaldehyde
Ethanol Ethyl acetate Formaldehyde
n-Heptane n-Hexane Isopropanol
Isopropyl acetate Methanol Methyl cellosolve
Methylene
chloride
Methyl isobutyl
ketone (MIBK)
Petroleum naptha
Phenol Toluene Triethylamine

8. Pharmaceutical Processes
(Biological and Natural Extraction)
 Products derived from natural sources – roots/leaves of
plants, animal glands, parasitic fungi, etc.
 Also include blood fractionation – production of plasma
and its derivatives
 These are too complex to synthesize commerically
 Usually requires collection and processing of large
quantities of specialised plant or animal matter to produce
small quantities of products
 Active ingredients extracted are generally present in raw
materials at very low levels
 Series of steps – volume of material in process reduces
significantly after almost every step
 Mostly, a unique assembly-line, small-scale batch
processing

9. Pharmaceutical Processes
(Biological and Natural Extraction)…
 Residual wastes mostly equal to weight of raw materials
 Solid wastes are greatest source of pollutant load
 Use of solvents in processing steps (sometimes used to
decontaminate material)
 Detergents and disinfectants used in equipment cleaning –
wastewater – use of phenols is prevalent
 Metals (Pb, Zn, etc.) used as precipitating agents
 Some extraction processes use ammonia where pH control
is necessary
 Principal sources of waste include;
 Spent raw material
 Chemical wastes
 Equipment and floor cleaning
 Cleanup of spills

10. Pharmaceutical Processes
(Biological and Natural Extraction)…
 Commonly used solvents
Acetone Acetonitrile Ammonia (aq.)
n-Amyl acetate Amyl alcohol n-Butyl alcohol
1,2-Dichloroethane Chloroform Diethylamine
N,N-Dimethylformaldehyde Methyl isobutyl ketone
(MIBK)
1,4-Dioxane
Dimethyl sulfoxiide Diethyl ether Ethylene glycol
Ethanol Ethyl acetate Formaldehyde
n-Heptane n-Hexane Isopropanol
Isopropyl acetate Methanol Pyridine
Methylene chloride N-propanol Petroleum naptha
Phenol Toluene Tetrahydrofuran

11. Pharmaceutical Processes
(Chemical Synthesis)
 Use organic and inorganic chemical reactions
 Most of the active ingredients marketed/sold as drugs
 Conventional batch reaction vessel
 Reaction vessels may be fitted with different attachments –
depending on process needs
 Common modifications for additional uses;
 Heating/refrigeration medium
 Reflux condensation equipment
 Vacuum
 Perform solvent extraction/crystallization operations
 Common attachments – filter, centrifuge, solvent recovery
header, etc.
 Usually product is manufactured in a “campaign”
 Same equipment can be utilized for manufacturing
different products

12. Pharmaceutical Processes
(Chemical Synthesis) …ATypicalReactor

13. Pharmaceutical Processes
(Chemical Synthesis) …
 Most of the industries have solvent recovery units
 SRU operation result in aqueous wastes fully or partially
saturated with residual solvent
 Wastewater is generally produced with each chemical
modification – requiring filling and emptying of reactors
 Wastewaters contain – unreacted raw materials, some
solvents, along with number of compounds
 The pollutants vary w.r.t. toxicity and biodegradability
 Principal sources of waste include;
 Process wastes – spent solvents, filtrates, concentrates, etc.
 Pump seal water
 Equipment and floor cleaning
 Spills
 APCE blowdown

14. Pharmaceutical Processes
(Chemical Synthesis)…
 Commonly used solvents (additional)
Aniline Benzene 2-Butanone (MEK)
n-Butyl acetate Chlorobenzene Chloromethane
Cyclohexane 1,2-Dichlorobenzene 1,2-Dichloroethane
Diethylamine Diethyl ether N,N-Dimethyl acetamide
Dimethylamine N,N-Dimethylaniline Formamide
Furfural Isobutyraldehyde Methylamine
Methyl formate MIBK 2-Methylpyridine
Triethylamine Trichlorofluoromethane Polyethylene glycol 600
Xylenes

15. Pharmaceutical Processes
(Mixing, Compounding & Formulating)
 Converting pharmaceutical active ingredients (produced
in bulk) to dosage (usable) form for consumer use – tablets,
capsules, liquids, and ointments
 Tablets – need blending with filler and binder (lubricants
also sometimes). Some tablets use solvent based coatings
 Capsules use hard gelatine shell
 Liquid preparations are formulated for injection or oral use
 Need sterilization sometimes
 Principal sources of waste include;
 Equipment and floor cleaning
 Spills and breakage
 Broken tablets – reused in granulation
 Improper capsules – remelted and reused or sold for glue
manufacture

16. Pharmaceutical Manufacturing Process
Variability
 Waste generation (quantitatively and qualitatively) can be
highly variable
 Factors contributing to variability
 Campaigning
 Batch processing
 Waste commingling

17. Utilities in Pharmaceutical
Manufacturing
 Water treatment – RO, DM, EDI, etc.
 Compressed air
 Process heating – steam generation/distribution, thermic
fluid heater
 Process cooling – cooling water, chiller, brine-water
 Work environment conditioning
 Cleaning – including CIP
 Air pollution control equipment
 Vacuum system
 Solvent recovery
 Effluent treatment
 Thermal destruction – incineration, MEE, drier

18. Water Use and Wastewater generation
in Pharmaceutical Manufacturing
 As product – becomes a part of final product
 Water of reaction – water formed during chemical reaction
 Process solvent – used to transport or support chemicals
involved in reaction process
 Water is usually removed – centrifugation, decanting, filtration,
drying, stripping, etc.
 Process stream wash
 Product wash
 Spent acid/caustic
 Condensed steam
 APCE blow-down
 Process cleaning, washing and housekeeping
 Pump seal water
 Non-contact cooling blow-down

19. Wastewater Characterization
 Mixing, compounding and formulation
 May contain carbohydrates and inert formulating material
 Low to moderate in BOD
 Low TSS
 Around neutral pH
 Fermentation
 ~2-10 m5/kg of final product
 Mycellium cake – wet cake has 40-70 g/l of BOD and 30-50 g/l
of TSS
 BOD – 2500-1000 mg/l
 pH – 4-8
 Vaccination, microbial suspension, antitoxin preparation
 Wastes contain very high BOD/COD and bad odours
 Antiseptic and anti-bacterial agents contribute to toxicity

20. Wastewater Characterization …
 Chemical synthesis
 General process liquor
 High strength process liquor
 Acidic and alkaline effluent
 Emulsified effluent
 Toxic effluent

21. Composition of Pharmaceutical Process
Wastes
Waste Description Process Origin Composition
Process liquors Chemical synthesis Contaminated solvents
Spent fermentation
broth
Fermentation processes Contaminated waters
Spent natural product,
raw materials
Natural product,
extraction processes
Plant residues, tissues
Spent aqueous solutions Solvent extraction
processes
Contaminated water
Leftover raw material,
containers
Unloading of materials
into process equipment
Bags/drums (fibre,
plastic, metal), plastic
bottles
Scrubber water from
APCE
Dust or hazardous
vapour generation
process
Contaminated water

22. Composition of Pharmaceutical Process
Wastes …
Waste Description Process Origin Composition
Volatile organic
compounds
Chemical storage tanks,
drums
Solvents
Off-spec or out-dated
products
Manufacturing
operations
Miscellaneous
chemicals
Spillages Manufacturing and
laboratory operations
Miscellaneous
chemicals and heavy
metals
Wastewater Equipment cleaning,
extraction residues
Contaminated water,
phenol based
Spent solvents Solvent extraction or
wash practices
Contaminated solvents
Used production
materials
Manufacturing
operations
Filters, tubing,
diatomaceous earth

23. Composition of Pharmaceutical Process
Wastes …
Waste Description Process Origin Composition
Used chemical reagents R&D activities Miscellaneous
chemicals, solvents,
acid/alkaline wastes,
radio-isotopes,
formaldehyde
Spent ethylene oxide Sterilization operations Ethylene oxide
Miscellaneous wastes Maintenance operations Waste lube oils,
vacuum pump oils,
cleaning solvents, paint
stripping wastes,
leftover paints and
accessories, spent
flourescent lamps, trash

24. Composition of Pharmaceutical Process
Wastes …
Waste Description Process Origin Composition
Used packaging
material
Packaging operations Plastic, wood,
cardboard, foam
products
Infectious/medical
wastes
R&D, manufacturing
operations, off-spec
products
Vials, biomass, blood
products, human/animal
specimens
Incinerator exhaust On-site incinerators Metals, oxides
Combustion products Boilers, thermic fluid
heater
Carbon compounds,
oxides of N & S, boiler
blow-down, cooling
tower sludges, and
sediments

25. Conventional approach;
 Waste collection
 Treatment for compliance (and to make the waste
compatible for disposal)
 Dispose
Alternative thoughts;
 Cheapest available solution just avoiding prosecution
 Best available solution not entailing excessive cost
Waste Management
Spend resources or face penalty

26. Source Reduction
 Material substitution
 Process modification
 Good operating practices
Waste Management
(Waste Minimization)

27. Waste Management
(Waste Minimization) …
Waste Waste Minimization Option
Containers Return empties to suppliers
Thoroughly empty and triple rinse with minimal water
Use containers with recyclable liners
Segregate solid waste
Collect and reuse plastic from in-house molding
Air
emissions
Control bulk storage air emissions
Use dedicated dust collectors & rework dust back into product
Optimize fossil fuel combustion
Use dedicated vent condensers & return condensate to source,
where possible
Maintain N2 purge rates at minimum through vapour space of
agitated reactors

28. Waste Management
(Waste Minimization) …
Waste Waste Minimization Option
Equipment
cleaning
wastes
Maximize number of campaigns to reduce cleaning frequency
Use final rinse as pre-rinse on next cleaning cycle
Use wiper blades & squeezes and rework remainders into
products
Use low volume, high efficiency cleaning (e.g., spray heads)
Spills and
area
washdown
Use dedicated vacuum systems
Use dry-cleaning methods
Use recycled water
Off-spec
products
Rework off-spec material
Use automated processing systems

29. Waste Management
(Waste Minimization) …
Waste Waste Minimization Option
Solvents Substitute with aqueous systems where possible
Reduce quantity of solvent used
Regenerate/recover spent solvent
Production
materials
Validate cleaning and reuse

30. Waste Management
(Good Operating Practices)
Plant Management Waste Management Material handling
Management incentives Waste/environmental
audits
Material tracking &
inventory control
Employee training Waste stream
segregation
Spill prevention
Closer supervision Waste handling and
storage procedures
Material handling &
storage procedures
Production scheduling Preventive maintenance
Additional
documentation